Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain?

Abstract

Neuropathic pain is a common clinical condition. Current treatments are often inadequate, ineffective, or produce potentially severe adverse effects. Understanding the mechanisms that underlie the development and maintenance of neuropathic pain will be helpful in identifying new therapeutic targets and developing effective strategies for the prevention and/or treatment of this disorder. The genesis of neuropathic pain is reliant, at least in part, on abnormal spontaneous activity within sensory neurons. Therefore, voltage-gated sodium channels, which are essential for the generation and conduction of action potentials, are potential targets for treating neuropathic pain. However, preclinical studies have shown unexpected results because most pain-associated voltage-gated channels in the dorsal root ganglion are down-regulated after peripheral nerve injury. The role of dorsal root ganglion voltage-gated channels in neuropathic pain is still unclear. In this report, we describe the expression and distribution of voltage-gated sodium channels in the dorsal root ganglion. We also review evidence regarding changes in their expression under neuropathic pain conditions and their roles in behavioral responses in a variety of neuropathic pain models. We finally discuss their potential involvement in neuropathic pain.

Figure 1

Involvement of dorsal root ganglion (DRG) channels and receptors in the induction and modulation of pain. A variety of DRG channels and receptors are involved in the transduction of noxious stimuli into electric impulses at the peripheral terminals of DRG neurons [e.g., transient receptor potential (TRP) channels, voltage-sensitive sodium (Na⁺) channels, ATP-sensitive receptors, acid sensing ion channels], in the conduction of action potentials along the axons [e.g., voltage-sensitive Na⁺ channels and potassium (K⁺) channels], and in the modulation of neurotransmitter release at presynaptic terminals of primary afferents in the dorsal horn [e.g., voltage-gated calcium (Ca²⁺) channels, GABA receptors, and glutamate receptors].

Figure 2

Schematic representation of signaling pathways that modulate Na⁺ channels (Nav). The activation of G-protein-coupled receptors (GPCR) by their ligands activates adenylyl cyclase (AC) and phospholipase C (PLC), which produce cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG), respectively. cAMP then activates cAMP-dependent protein kinase (PKA), whereas DAG activates protein kinase C (PKC). Both PKA and PKC phosphorylate (P) the Na⁺ channel to regulate its function.

Figure 3

Potential mechanisms by which sodium channel (Nav) expression is regulated. Neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF) bind to their respective receptors: tyrosine kinase receptor (Trk) A, TrkB, and Ret; receptor stimulation then activates the Ras/MEK/MAPK pathway. Activated MAPK promotes expression of sodium channels at the levels of mRNA and protein through unknown mechanisms (indicated by the red dashed arrows). An inflammatory cytokine, tumor necrosis factor α (TNFα), also up-regulates expression of sodium channels through activation of the TRAF2/MEK/MAPK pathway. In contrast, neurotrophin-3 (NT-3) down-regulates the expression of sodium channels through TrkA-mediated inhibition of the Ras/MEK/MAPK pathway (indicated by the blue dashed arrows). MAPK: mitogen-activated protein kinases; MEK: MAPK kinase; TNFR1: tumor necrosis factor receptor 1; TRAF2: TNF receptor-associated factor 2.